Pure spastic paraparesis associated with a novel presenilin 1 R278K mutation

Abstract

The early-onset familial AD (EOFAD) linked to presenilin 1 ( PS1 ) mutations show a heterogeneous phenotype that is illustrated mainly by the coexistence of dementia with spastic paraparesis, described in a few kindreds.1-3⇓⇓ The altered processing of amyloid precursor protein, favoring the production of the longer amyloid β-peptide form ending at residue 42 (Aβ42), is the major pathogenic effect of PS1 mutations.4 The relationship between clinical phenotype and Aβ42 production is unclear. We report a kindred bearing a novel PS1 mutation that showed an extremely wide clinical spectrum among the three affected members. A 45-year-old woman (I-1) showed progressive paraparesis followed after 5 years by dementia. She died at age 57, and autopsy was not performed. Her daughter (II-2) presented at 48 years with delusional thinking followed by progressive impairment of all cognitive functions. Neurologic examination at 55 years did not reveal loss of strength or pyramidal signs at the limbs. Her brother (II-3) became symptomatic at the …